Farnesol: The farnesylator of PARIS

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A build up of “PARkin Interacting Substrate” (or PARIS) protein has been proposed as one potential mediator of the pathology observed in some cases of Parkinson’s. The accumulation of this protein leads to the inhibition of a key protein called PGC-1α, which is a neuroprotective protein that helps to keep cells alive.

For sometime, researchers have been searching for molecules that can act as inhibitors of PARIS, in the hope that blocking PARIS would allow PGC-1α to act freely. Such an agent could have potential as novel treatment for Parkinson’s.

This week a research report was published that describes one possible PARIS inhibitor. It is called farnesol.

In today’s post, we will look at the biology behind PARIS, review the new report, and discuss what exactly is known about farnesol.

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Pont Royal et Musée d’Orsay. Source: Wikipedia

Paris has a special place in my heart for several reasons.

The main one: I proposed to my wife there on the Pont Royal.

We had planned a day out in London, but once we got down to Waterloo “for lunch at a special restaurant“, I surprised her with two Euro Star tickets and we were off on the train for Paris – just like that (I might look the hardened tough guy on the outside, but deep down I am really just a tragic romantic).

And that night, after “dinner at a special restaurant” shortly before 10pm as we were crossing the middle of the Pont Royal, and a small miracle occurred: the traffic lights stopped traffic in both directions.

Source: Pixels

Seizing our chance moment alone, I dropped to one knee and asked (read: begged).

Now, if she had said ‘no thanks‘, I had a back up plan: Jump over the side of the bridge, float down the Seine some ways, climb out and then join the Foreign Legions the next day as a mute (je suis muet”).

But she didn’t say no (let’s call that the second small miracle) and thankfully for my fragile ego’s sake there wasn’t a lengthy deliberation.

When the traffic lights changed and traffic started to flow again, we received some enthusiastic honks of the klaxons (horns) as I got up and we headed off to alert our parents. It was a really nice moment.

I was recalling this moment, this week when a different type of Paris was being discussed in the news.

What do you mean “a different type of Paris”?

Continue reading “Farnesol: The farnesylator of PARIS”

The Bluerockers have started

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On the 8th June, BlueRock Therapeutics put out a press release announcing that the first participant in their Phase I clinical trial of cell transplantation for Parkinson’s had been dosed (Click here to read the press release).

The initiation of this clinical trial by the company is a major step forward for them and for the wider field of regenerative therapies.

In today’s post, we will look at what cell transplantation is, recent developments in clinical trials, and what the immediate future holds. 

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Source: The Scientist

Here on the SoPD, we work around the idea that any “curative therapy” for Parkinson’s is going to require three core components:

  1. A disease halting mechanism
  2. A neuroprotective agent
  3. Some form of restorative therapy

Parkinson’s is a progressive neurodegenerative condition, meaning that symptoms are gradually going to get worse over time. Thus, the first and most critical component of any ‘cure’ for Parkinson’s involves a treatment that will slow down or halt the progression of the condition.

Once such a therapy has been identified, it will be necessary to rejuvenate and protect the remaining cells. So, some form of neuroprotective therapy that can help bring sick or dying cells back to life will be required.

Such a treatment will also provide a nurturing environment for the third part of the ‘cure’: A restorative treatment. New cells will be required to replace the lost function.

Now, the bad news is (as far as I am aware) there is no single treatment currently available (or being tested) that can do all three of these things. By this I mean that there is no “disease halting mechanism” therapy that can also replace lost brain cells. Nor is there a restorative therapy that stop the progression of the condition.

That statement can obviously be read as terrible news, but it shouldn’t.

Let me explain:

Continue reading “The Bluerockers have started”

The Anavex results

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This week some encouraging clinical trial results were announced by a biotech firm called Anavex Life Sciences.

The company had been testing their lead experimental therapy – a Sigma-1 receptor agonist called ANAVEX2-73 (also known as blarcamesine) – in 132 people with Parkinson’s disease dementia over a 14 week period.

The results are rather encouraging: significantly positive outcomes in both cognitive and motor symptoms.

In today’s post, we will explain what exactly “Sigma-1 receptor agonist” means, discuss what Parkinson’s disease dementia is, and review what we currently know about the results of the trial.

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Source: Pumpingmarvellous

A lot of clinical trials for disease modification in Parkinson’s are focused on targeting well known proteins that are believed to be associated with underlying biology of the condition, such as alpha synuclein, LRRK2, and GBA. We discuss these on a regular basis here on the SoPD.

There are, however, a large number of trials investigating less well known targets.

And this week we received news that one of these clinical trials had some positive results.

Source: Thestreet

The study was conducted by the biotech company Anavex Life Sciences and it involved their lead experimental therapy ANAVEX2-73 (also known as blarcamesine).

ANAVEX2-73 is a Sigma-1 receptor agonist.

What does that mean?

Continue reading “The Anavex results”

EJS-ACT PD

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This week an announcement was made regarding The Edmond J. Safra Accelerating Clinical Treatments for Parkinson’s Disease (EJS-ACT PD) Initiative.

It is hoping to revolutionise the way clinical trials for potentially disease-modifying drugs for Parkinson’s are conducted.

The project is focused on the setting up a multi-arm, multi-stage (MAMS) platform for evaluating new therapies for PD.

In today’s post, we will discuss what MAMS trials involve and the current details of the EJS-ACT PD initiative.

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Source: Motionarray

This week I boarded a train for the first time in 16 months and made my way down to London. It felt a wee bit surreal.

I arrived at Liverpool street station and was immediately shocked by the lack of crowds, the lack of face masks (seriously?!? I’ve had my two jabs as well, but I’m still wearing my mask – you are nuts if you don’t!), and the large number of empty shops. How the world has changed.

In the early morning light, I walked across central London towards St Pancras station – the weather was spectacular and it was an incredible pleasure to stroll through some old stomping grounds.

Source: Parksandgardens

At St Pancras station, I made my way to the enormous Francis Crick institute, where a group of Parkinson’s researchers and advocates were gathering for a really intriguing meeting.

Source: Timeshighereducation

What was the meeting about?

Continue reading “EJS-ACT PD”

Unmasking LRRK2 and GBA

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Connecting genetics and biology is complicated. Researchers around the world have struggled to determine what each functional region of DNA is doing individually, let alone in combination with other regions.

And sometimes when the output of combinations is examined, the results can be unexpected.

Recently, researchers looked at the consequences of having a particular combination of Parkinson’s-associated risk factors… and they were rather surprised by the results

In today’s post, we will review the report presenting their results and consider the potential implications of the findings.

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Bragging rights. Source: Howstuffworks

A while back, I became a little obsessed with peacock feathers.

I didn’t start collecting them and wearing them on Saturday night or anything like that. Rather, I just got really fascinated with how they develop. Each individual feather, that is.

I mean, look at them:

Source: Dreamingandsleeping

Like all organisms, they are wondrous feats of nature and biology – particularly the jewel-toned ocelli (plural) or eyespots (the vivid circular patterns that seem evenly spread along each feather).

Each ocellus (singular) is created via a combination of individual strands of the larger feather. And each strand is further made up of tiny individually coloured segments. When you get really up close and personal with those eyespots, they look like this:

Source: Wired

My obsession centered around “the how”.

How does each strand of the feather know when to start some blue or gold colouration (and when to stop) along those strands? And how do the individual strands coordinate and match up so perfectly to create the marvelous image of the ocellus?

This type of question applies to many areas of biology (for example, how does a regenerating tail of a gecko know when to stop growing?), but remember that at the end of each mating season, the peacock sheds (or molts) its feathers. So these carefully coordinated feathers have to re-grow each year!

Tell me that that is not remarkable.

Remarkable, but what does this have to do with Parkinson’s?

Continue reading “Unmasking LRRK2 and GBA”

UCB at ANN looks A-OK

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Alpha synuclein is one of the most common proteins in our brains and it has long been associated with Parkinson’s. The protein appears to clump together forming dense clusters ( or “aggregates“) in the Parkinsonian brain, and this may be related to the progressive neurodegeneration.

Researchers have been desperately seeking small molecules that will break up (or dissociate) these aggregates in the hope that it will slow down the progression of PD and allow neurons to return to health.

One example of such a molecule is UCB0599, which is being clinically developed by the pharmaceutical company UCB. This week, UCB presented the first clinical results for UCB0599 from their Phase I trial.

In today’s post, we will look at what alpha synuclein is, review what is known about UCB0599, discuss the results of the study, and consider what comes next.

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Source: AAN

Last week at the 2021 American Academy of Neurology virtual meeting a poster was presented by the pharmaceutical company UCB.

Here at SoPD HQ, we have been eagerly awaiting these results.

They were the findings from the first Phase I clinical trial of a new molecule called UCB0599.

What is UCB0599?

UCB0599 is a brain-penetrant, oral small molecule alpha-synuclein misfolding inhibitor.

What does that mean?

Continue reading “UCB at ANN looks A-OK”

What is GDNF without RET?

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Neurotrophic factors – like Glial cell line-derived neurotrophic factor (or GDNF) – hold great hope for regenerative therapy in Parkinson’s research. New research, however, indicates that simply injecting the protein into the brain may not be enough.

Scientists at Rush University Medical Center (in Chicago) conducted a postmortem analysis of brains from people who passed away with Parkinson’s and made an intriguing discovery.

They found that many of the remaining dopamine neurons appear to not be producing a protein called Ret, which is required for GDNF signaling. In addition, other components of GDNF signaling pathway were missing. 

In today’s post, we will review the background of this new study, outline what the study found, and discuss the implications of the research.

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GDNF. Source: Wikipedia

Glial cell line-derived neurotrophic factor (or GDNF) is a topic that gets a lot of reader attention on the SoPD. It is a tiny protein that holds great hope for the Parkinson’s community in terms of providing a potential neuroprotective and regenerative therapy.

GDNF is a type of neurotrophic factor, which are small naturally-occurring proteins that nurture neurons and support their growth. There are different kinds of neurotrophic factors, and the testing of some of them in preclinical models of Parkinson’s has generated encouraging results (particularly in the case of GDNF – click here to read a previous SoPD post on this topic).

But the translation of those initial results in cell culture and animal models of Parkinson’s has been difficult in clinical trials of neurotrophic factors.

This has led to many questions being asked within the research community about the nature of biological signaling pathways involved with neurotrophic factors and whether they might be affected in Parkinson’s.

The majority of the neurotrophic factors that have been tested in models of Parkinson’s and in clinical trials for Parkinson’s belong to a branch that requires the RET signaling pathway to be available to have their neuroprotective effect.

What is the RET signaling pathway?

Continue reading “What is GDNF without RET?”

Trying to LIMP-2 the lysosome

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Lysosomes are small bags of enzymes that are used to break down material inside of cells – digesting newly absorbed food or recycling old/used proteins and rubbish. Recently researchers have been discovering increasing evidence that points towards dysfunction in lysosomes as a key influential player in neurodegenerative conditions, like Parkinson’s.

There are several Parkinson’s genetic risk factors associated with lysosomal function (GBA being the obvious one), that can increase one’s risk of developing Parkinson’s.

But there is also data indicating that individuals without any of these risk factors may also have reduced lysosomal activity. And recently researchers have identified one possible explanation.

In today’s post, we will explore what lysosomes are, investigate how they maybe involved with Parkinson’s, review what the new data reports, and discuss how this information might be useful.

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Type of endocytosis. Source: Slidemodel

On a continual basis, cells inside your body are absorbing material from the world around them with the aim of collecting all that they need to survive. They do this predominantly via a process called endocytosis, in which a small part of the cell membrane envelopes around an object (or objects) and it is brought inside the cell.

As the section of cell membrane enters the interior of the cell, it detaches from the membranes and forms what is called an endosomes (sometimes it is also called a vacuole). Once inside, the endosome transported deeper into the interior of the cells where it will bind to another small bag that is full of digestive enzymes that help to break down the contents of the endosome.

This second bag is called a lysosome.

Lysosomes

How lysosomes work. Source: Prezi

Once bound, the lysosome and the endosome/vacuole will fuse together and the enzymes from the lysosome will be unleashed on the material contained in the vacuole. The digestion that follows will break down the material into more manageable components that the cell needs to function and survive.

This enzymatic process works in a very similar fashion to the commercial products that you use for washing your clothes.

Enzymatic degradation. Source: Samvirke

The reagents that you put into the washing machine with your clothes contain a multitude of enzymes, each of which help to break down the dirty, bacteria, flakes of skin, etc that cling to your clothes. Each enzyme breaks down a particular protein, fat or such like. And this situation is very similar to the collection of enzymes in the lysosome. Each enzyme has a particular task and all of them are needed to break down the contents of the endosome.

Interesting, but what does this have to do with Parkinson’s?

Continue reading “Trying to LIMP-2 the lysosome”

The road ahead: 2021

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At the start of each year, it is a useful practise to layout what is planned over the next 12 months. The events that are scheduled for the year to come, so that we can keep an eye out for them. Obviously, where 2021 will end actually is unpredictable, but an outline of what is scheduled over the next 365 days will hopefully provide us with a useful resource for helping to manage expectations.

Here at the SoPD, we are primarily interested in disease modification for Parkinson’s. While there is a great deal of interesting research exploring the causes of the condition, the genetics and biology of the condition, novel symptomatic therapies, and other aspects of Parkinson’s, my primary focus is generally on the science seeking to slow, stop or reverse the condition.

In this post, I will try to map out some of what is scheduled to occur in 2021 with regards to clinical research focused on disease modification for Parkinson’s. I will also note aspects of ongoing research where I will be hoping to see an update on progress. It will be an extremely (read: ridiculously) long post, but it will hopefully give readers a feel for what the landscape looks like for research focused on disease modification for Parkinson’s.

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Source: Kickstarter

Cartography is the study and practice of mapping things out. It has been used for centuries to provide graphic representations of what stuff looks like to help us to better understand things.

The word cartography comes from the Greek words χάρτης or chartēs (meaning “papyrus, sheet of paper”) and γράφειν or graphein (meaning “to write”).

According to Wikipedia, the fundamental objectives of traditional cartography are to:

  • Set the map’s agenda and select traits of the object to be mapped.
  • Represent the terrain of the mapped object on flat media.
  • Eliminate characteristics of the mapped object that are not relevant to the map’s purpose.
  • Reduce the complexity of the characteristics that will be mapped.
  • Orchestrate the elements of the map to best convey its message to its audience.

At the start of each year, the SoPD publishes a horizon scanning post where we take a cartography-like approach towards laying out the landscape of clinical research focused on disease modification for Parkinson’s for the next 12 months.

Source: Rand

We try to “set the agenda” and “select traits” to look out for in 2021. We also try to “represent the terrain” and “reduce the complexity of the characteristics” (well,… at least we will try to!) in a manner that will “best convey” to the reader what the next 12 months may look like.

All of this is in an effort in better managing expectations about some of the research results that are coming down the pipe.

Continue reading “The road ahead: 2021”

TGF-beta: The Parkinson’s superfamily?

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A lot of Parkinson’s research has focused on a neurotrophic factor called glial cell-derived neurotrophic factor (or GDNF).

But GDNF only represents a small fraction of a much larger class of neurotrophic factors, called the Transforming growth factor-β (TGF-β) superfamily.

Recently, researchers have been investigating some of the other TGF-β family members in preclinical models of Parkinson’s and they have been making some interesting discoveries.

In today’s post, we will discuss what is meant by neurotrophic factor, explore who else is in the TGF-β superfamily, and look at two recent reports highlighting family members in the context of Parkinson’s.

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Different types of cells in the brain. Source: Dreamstime

Glial cells are the support cells in the brain. While neurons are considered to be the ‘work horses’ of neurological function – passing messages and storing memories – glial cells are in the background making sure that neurons are protected and well nurtured.

There are different types of glial cells, including astrocytes, oligodendrocytes and microglia. And each type has a specific function, for example microglia are the brain’s resident immune cells checking up on the health of the neurons while oligodendrocytes provide the neurons with a protective covering (called myelin sheath) which also helps to speed up the signalling of neurons.

A human astrocyte. Source: Wikipedia

Astrocytes provide nutrients and neurotrophic factors to neurons and make sure the environment surrounding the neurons is balanced and supportive. Glial cells are absolutely critical to the normal functioning of the brain.

What are neurotrophic factors?

Continue reading “TGF-beta: The Parkinson’s superfamily?”